WO2013075399A1 - Composé benzo-hétérocyclique à 5 chaînons non saturé ou ses sels pharmaceutiquement acceptables, procédé de préparation associé, composition pharmaceutique et utilisation associée - Google Patents
Composé benzo-hétérocyclique à 5 chaînons non saturé ou ses sels pharmaceutiquement acceptables, procédé de préparation associé, composition pharmaceutique et utilisation associée Download PDFInfo
- Publication number
- WO2013075399A1 WO2013075399A1 PCT/CN2012/001555 CN2012001555W WO2013075399A1 WO 2013075399 A1 WO2013075399 A1 WO 2013075399A1 CN 2012001555 W CN2012001555 W CN 2012001555W WO 2013075399 A1 WO2013075399 A1 WO 2013075399A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- carboxylic acid
- ester
- dimethylamine
- substituted
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 230000003262 anti-osteoporosis Effects 0.000 claims abstract description 6
- -1 isovaleryl Chemical group 0.000 claims description 126
- 125000004494 ethyl ester group Chemical group 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 125000005605 benzo group Chemical group 0.000 claims description 34
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 34
- 150000004702 methyl esters Chemical class 0.000 claims description 33
- 125000002252 acyl group Chemical group 0.000 claims description 31
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 28
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 23
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 22
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 20
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 19
- ZFQAAMGCGJKDSV-UHFFFAOYSA-N furo[2,3-f][1,3]benzodioxole-6-carboxylic acid Chemical compound C1=C2OC(C(=O)O)=CC2=CC2=C1OCO2 ZFQAAMGCGJKDSV-UHFFFAOYSA-N 0.000 claims description 19
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 19
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- DDYQAKGAKIASSJ-UHFFFAOYSA-N thieno[2,3-f][1,3]benzodioxole-6-carboxylic acid Chemical compound C1=C2SC(C(=O)O)=CC2=CC2=C1OCO2 DDYQAKGAKIASSJ-UHFFFAOYSA-N 0.000 claims description 15
- IQELKSYGXWBQJA-UHFFFAOYSA-N 6-methoxy-1-benzofuran-2-carboxylic acid Chemical compound COC1=CC=C2C=C(C(O)=O)OC2=C1 IQELKSYGXWBQJA-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 claims description 13
- XTXMOIBADXDEKF-UHFFFAOYSA-N 6-methoxy-1-benzothiophene-2-carboxylic acid Chemical compound COC1=CC=C2C=C(C(O)=O)SC2=C1 XTXMOIBADXDEKF-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- YMZTUCZCQMQFMK-UHFFFAOYSA-N 3-methyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(C)=C(C(O)=O)OC2=C1 YMZTUCZCQMQFMK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004185 ester group Chemical group 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- OSBSXTGABLIDRX-UHFFFAOYSA-N 5-methylidenecyclohexa-1,3-diene Chemical compound C=C1CC=CC=C1 OSBSXTGABLIDRX-UHFFFAOYSA-N 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000004442 acylamino group Chemical group 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 7
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 6
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000006612 decyloxy group Chemical group 0.000 claims description 6
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- QSJOOKNQBKWMAP-UHFFFAOYSA-N 1-benzofuran-2,6-dicarboxylic acid Chemical compound OC(=O)C1=CC2=CC=C(C=C2O1)C(O)=O QSJOOKNQBKWMAP-UHFFFAOYSA-N 0.000 claims description 4
- DHNVMKHYFMDCPG-UHFFFAOYSA-N 6-acetyl-1-benzofuran-2-carboxylic acid Chemical compound C(C)(=O)C1=CC2=C(C=C(O2)C(=O)O)C=C1 DHNVMKHYFMDCPG-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000005251 aryl acyl group Chemical group 0.000 claims description 4
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 4
- 150000003935 benzaldehydes Chemical class 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000012024 dehydrating agents Substances 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- ANSUPYBJVNMSJB-UHFFFAOYSA-N 5,6-dimethoxy-1-methylindole-2-carboxylic acid Chemical compound C1=C(OC)C(OC)=CC2=C1N(C)C(C(O)=O)=C2 ANSUPYBJVNMSJB-UHFFFAOYSA-N 0.000 claims description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 3
- 229940124605 anti-osteoporosis drug Drugs 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- LOIHKMZAAYGFGR-UHFFFAOYSA-N (6-methoxy-1-benzofuran-2-carbonyl)oxymethylphosphonic acid Chemical compound P(=O)(O)(O)COC(=O)C=1OC2=C(C1)C=CC(=C2)OC LOIHKMZAAYGFGR-UHFFFAOYSA-N 0.000 claims description 2
- NQJCVIXMLHCDDC-UHFFFAOYSA-N (6-methoxy-1-benzothiophene-2-carbonyl)oxymethylphosphonic acid Chemical compound COC1=CC=C2C=C(C(=O)OCP(O)(O)=O)SC2=C1 NQJCVIXMLHCDDC-UHFFFAOYSA-N 0.000 claims description 2
- JOJJJXBBKZHGFN-UHFFFAOYSA-N 1-(2-hydroxyethyl)-5-methoxyindole-2-carboxylic acid Chemical compound COC1=CC=C2N(CCO)C(C(O)=O)=CC2=C1 JOJJJXBBKZHGFN-UHFFFAOYSA-N 0.000 claims description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 claims description 2
- GSWKZAVAIDGPKF-UHFFFAOYSA-N 2-(6-methoxy-1-benzofuran-2-carbonyl)oxyethylphosphonic acid Chemical compound COC1=CC=C2C=C(C(=O)OCCP(O)(O)=O)OC2=C1 GSWKZAVAIDGPKF-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- PSJMNAIMOCVKGC-UHFFFAOYSA-N 3-ethyl-1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2C(CC)=C(C(O)=O)OC2=C1 PSJMNAIMOCVKGC-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005921 isopentoxy group Chemical group 0.000 claims description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical group COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000002430 hydrocarbons Chemical group 0.000 claims 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical group NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical class CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 claims 1
- 150000001735 carboxylic acids Chemical group 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- CSMFSDCPJHNZRY-UHFFFAOYSA-N decyl hydrogen sulfate Chemical compound CCCCCCCCCCOS(O)(=O)=O CSMFSDCPJHNZRY-UHFFFAOYSA-N 0.000 claims 1
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 229950009195 phenylpropanol Drugs 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 22
- 208000001132 Osteoporosis Diseases 0.000 abstract description 21
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 abstract description 16
- 230000003827 upregulation Effects 0.000 abstract description 9
- 241000699670 Mus sp. Species 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- 208000024891 symptom Diseases 0.000 abstract description 3
- 230000004821 effect on bone Effects 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 31
- 239000000203 mixture Substances 0.000 description 25
- 239000007858 starting material Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000005457 ice water Substances 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 102000008143 Bone Morphogenetic Protein 2 Human genes 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000002994 raw material Substances 0.000 description 12
- 210000000988 bone and bone Anatomy 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 210000000963 osteoblast Anatomy 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- 239000002674 ointment Substances 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- TZPPDWDHNIMTDQ-UHFFFAOYSA-N 2-dimethoxyphosphorylethanol Chemical compound COP(=O)(OC)CCO TZPPDWDHNIMTDQ-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- RWIGWWBLTJLKMK-UHFFFAOYSA-N diethoxyphosphorylmethanol Chemical compound CCOP(=O)(CO)OCC RWIGWWBLTJLKMK-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- 230000011164 ossification Effects 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
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- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- 150000002611 lead compounds Chemical class 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
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- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
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- ZBELDPMWYXDLNY-UHFFFAOYSA-N methyl 9-(4-bromo-2-fluoroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Br)C=C1F ZBELDPMWYXDLNY-UHFFFAOYSA-N 0.000 description 1
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- 210000003098 myoblast Anatomy 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000002188 osteogenic effect Effects 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
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- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 108010023714 recombinant human bone morphogenetic protein-2 Proteins 0.000 description 1
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- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
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- 235000000346 sugar Nutrition 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
- C07F9/655354—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- Osteoporosis is a systemic bone mass characterized by microstructural destruction of bone tissue.
- osteoporosis caused by medication in HIV, cardiovascular disease and diabetes patients is becoming more and more serious. Osteoporosis and its complications have become a health problem that attracts the attention of the whole society. It is effective to prevent and treat osteoporosis. Drugs and treatments have also become research hotspots worldwide.
- osteoblasts obs
- osteoclasts ocs
- Osteoblast proliferation and differentiation are regulated by a variety of factors, including Bone Morphogenetic Protein-2 (BMP-2), which plays a key role in the differentiation of osteoblasts.
- BMP-2 also promotes the expression of other osteogenic factors, such as osteoinductive protein (OP), core binding factor al (Cbfal), alkaline phosphatase (ALP), and fatty acid coupling. Protein 4 (fabp4), etc.
- OP osteoinductive protein
- Cafal core binding factor al
- ALP alkaline phosphatase
- fabricp4 Protein 4
- BMP-2 not only has a stimulatory differentiation effect on bone tissue-derived cell lines, such as osteoblast precursor cells, ROB-C26 cells, MC3T3-EK osteoblasts, W-20 bone marrow stromal cells, etc.
- bone tissue-derived cell lines such as osteoblast precursor cells, ROB-C26 cells, MC3T3-EK osteoblasts, W-20 bone marrow stromal cells, etc.
- non-bone tissue-derived cell lines such as pluripotent fibroblasts C3H10T1/2 and C212 myoblasts, differentiate into osteoblasts, and induce differentiation of osteoblasts and remodeling of young bones in mesenchymal cells.
- rhBMP-2 Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2, INFUSE® Bone Graft) for its role in promoting bone deposition and repairing long bones
- the present invention provides a series of benzo five-membered unsaturated heterocyclic compounds having a structure of the formula I or a pharmaceutically acceptable salt thereof, which has an activity of up-regulating the expression of bone morphogenetic protein BMP-2 and can be used for the treatment of osteoporosis.
- the invention also provides a preparation method of the benzo five-membered unsaturated heterocyclic compound.
- the present invention also provides the use of the benzo five-membered unsaturated heterocyclic compound in the treatment of osteoporosis and related patients caused by osteoporosis.
- the present invention also provides a pharmaceutical composition for treating osteoporosis, which comprises the above-mentioned benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- the benzo five-membered unsaturated heterocyclic ring of the present invention is a benzothiophene, benzofuran or an anthracene of a substituted 2-position carboxylic acid ester at a different position (3-, 4-, 5-, 6-, 7-) a compound of formula I which is a parent nucleus, a compound having a substituted ester group or a substituted amide group introduced at the 2-position, and a phenyl 5-membered unsaturated heterocyclic ring having an alkyl group, a halogen, an alkoxy group, an amino group, an acyl group Different substituents such as a carboxyl group and an ester group, and the effect of introducing a substituted ester group or a substituted amide group at the 2-position on the up-regulation of BMP-2 activity of the compound.
- the benzo five-membered unsaturated heterocyclic compound of the present invention has a structure represented by the formula I, wherein the benzene-unsaturated heterocyclic ring may have an alkyl group, a halogen, a decyloxy group, an amino group, an acyl group, a carboxyl group, an ester group or the like.
- Substituent; thiophene, furan ring or pyrrole moiety is a hydrocarbyl group, a carboxyl group, an acyl group, a decyloxy group, a sulfonic acid group, a phosphoric acid group, a sodium phosphate, a dihydrocarbylamine of 1 to 6 carbons, a morpholine, a piperidine, a N - Ethanylpiperazine, pyrrolidine, hydrocarbyl piperazine of 1 to 6 carbons, decahydropyrido[1,2 - ⁇ ]pyrazine, and the like.
- the present invention provides a benzo five-membered unsaturated heterocyclic compound having a structure represented by the formula I or a pharmaceutically acceptable salt thereof,
- X is selected from 0, S or NR 8 , wherein R 8 is selected from any one of H, a hydrocarbyl group, a halogenated hydrocarbyl group, a carbonyl hydrocarbyl group, a hydroxyhydrocarbyl group, an aminohydrocarbyl group, and a hydrocarbyloxy group;
- Y is selected from 0 or NR!'; wherein R!' is selected from any of H, -OH, a hydrocarbyl group, an acyl group, an alkoxy group, or a sulfonyl group; R 2 is selected from H or a C1-C6 dihydrocarbyl group;
- n 0-6 positive integer
- R 3 is selected from the group consisting of an anthracene, a hydrocarbon group, a halogen, an acyl group, a carboxyl group, an amino group, a substituted amino group, a sulfonic acid group, a nitrile group, and an acyl alkoxy group;
- R 5 , R 6 , and R 7 are each selected from the group consisting of H, a hydrocarbon group, an alkoxy group, a halogen group, a carboxyl group, an amino group, a substituted amino group, an acyl group, an ester group, and a sulfonic acid group;
- R 5 and R 6 are connected via a carbon, oxygen or nitrogen together, form a 5-7 membered ring structure or a 5-7 membered ring structure with a substituent group R 9, wherein, R 9 is selected from H, alkyl, haloalkyl Any one of a carbonyl hydrocarbon group, a hydroxy hydrocarbon group, an amino hydrocarbon group, and a hydrocarbyloxy group.
- the hydrocarbon group comprises a C1-C18 linear or branched alkyl group and a cycloalkyl group.
- the alkoxy group comprises a C1-C18 linear or branched alkoxy group.
- the acyl group comprises an acyl or aryl acyl group substituted by a linear or branched fluorenyl group of C1-C18.
- the ester group comprises an ester group or an aryl ester group substituted by a C1-C18 linear or branched fluorenyl group.
- the acylamino group comprises an acylamino or aryl acylamino group substituted by a C1-C18 linear or branched fluorenyl group.
- the C1-C18 linear or branched fluorenyl group comprises a C1-C18 linear or branched alkyl group selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, Any of n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl.
- the cyclodecyl group includes any one of cyclopentane and cyclohexan.
- the C1-C18 linear or branched alkoxy group includes a methoxy group, an ethoxy group, an isopropoxy group, a n-propoxy group, a n-butoxy group, and an isobutoxy group. Any of a group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, an isopentyloxy group, a n-hexyloxy group, and an isohexyloxy group.
- the acyl group substituted by a C1-C18 linear or branched fluorenyl group includes a formyl group, an acetyl group, an isopropyl group, a n-propyl group, an allyl group, a cyclopropyl group. Any of an acyl group, an n-butyl acyl group, an isobutyl acyl group, a sec-butyl acyl group, a t-butyl acyl group, a n-pentyl acyl group, an isopentyl acyl group, an n-hexyl acyl group, and an isohexyl acyl group.
- the aryl acyl group includes any one of a phenyl acyl group and a tolyl acyl group.
- the ester group substituted by a C1-C18 linear or branched alkyl group includes a formyloxy group, an acetoxy group, an isopropyl acyloxy group, a n-propyl acyloxy group, Allyloxy, cyclopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, iso Any one of a pentyl acyloxy group, a n-hexyl acyloxy group, and an isohexyl acyloxy group.
- the aryl ester group includes any one of a phenyl acyloxy group and a tolyl acyloxy group.
- the acylamino group substituted by a C1-C18 linear or branched fluorenyl group includes a methyl amide group, an ethyl amide group, an isopropyl amide group, a propyl propyl amide group, an olefin group.
- the arylamido group includes any one of a phenylamido group and a tolylamino group.
- the hydrocarbon group is a C1-C6 linear or branched alkyl group.
- the hydrocarbon group in the halogenated hydrocarbon group, the carbonyl hydrocarbon group, the hydroxy hydrocarbon group, the amino hydrocarbon group or the alkoxy group is any one of C1 to C6 hydrocarbon groups.
- the substituent of the substituted amino group is a C2-C6 fluorenyl group.
- the substituent is selected from a C1-C6 lower fluorenyl group, a lower decyloxy group, Any one of halogen, amino or a combination thereof.
- the benzo five-membered unsaturated heterocyclic compound includes a substituted benzofuranyl-2-substituted carboxylic acid ester, a substituted benzothienyl-2-substituted carboxylic acid ester, and a substituted hydrazine. Any one of a mercapto-2-substituted carboxylic acid ester, a substituted phenylpropanyl-2-yl substituted amide, and a substituted phenylpropenyl-2-substituted amide.
- the substituted benzofuranyl group includes a methoxy group, a dimethoxy group, Any one or a combination of a fluorenyl group, a halogen, a carboxyl group, an acetyl group, a sulfonic acid group, a methyl carboxylate, a methylene dioxy group, a diamino group of C1-C18.
- the substituent in the substituted benzothienyl group includes a methoxysulfonic acid group, a methyl carboxylate, a methylene dioxy group, a substituted methylene dioxy group, a diamino group. Any one or a combination thereof.
- the substituent in the substituted indenyl group includes any one of a substituted methoxy group, a substituted dimethoxy group, a dimethoxy group, or a combination thereof.
- the substituent in the substituted phenylpropanyl group includes any one of a methylene dioxy group, a methyl carboxylate or a combination thereof.
- the substituted phenylpropenyl-2-substituted amide comprises a methylene dioxy group.
- the substituted carboxylic acid ester comprises a carboxylic acid (diethyl 2,-phosphonate), a carboxylic acid (dimethyl 2,-phosphonate), a carboxylic acid (2,- Dimethylamine) Ethyl ester, carboxylic acid (2,-dimethylamine) propyl ester, carboxylic acid pyrrolidine ethyl ester, carboxylic acid piperidinyl ethyl ester, carboxylic acid morpholine ethyl ester, carboxylic acid (1,1-dimethyl Ethyl-2-dimethylamine) Ethyl ester, carboxylic acid [4,-(2"-hydroxyethyl)]piperazine ethyl ester, carboxylic acid phosphonyl methyl ester, and carboxylic acid phosphonyl ethyl ester or Its combination.
- the substituted amide comprises carboxylic acid (2,-dimethylamine) ethylamine, carboxylic acid (2,-dimethylamine-N-methyl)ethylamine, carboxylic acid (4) , -phosphonoethylidene methylene benzene) Any one or combination of an amine, a carboxylic acid (4'-phosphono sodium methylene benzene) amine.
- the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof comprises the following compounds:
- the benzo five-membered unsaturated heterocyclic compound having the structure of the formula I of the present invention is preferably improved in water solubility, metabolic stability and therapeutic activity, and has an activity of up-regulating BMP-2 protein expression and promoting bone formation.
- the activity becomes a novel anti-osteoporosis drug or its lead compound.
- the benzothiophene/furan or anthraquinone compound of the benzo five-membered unsaturated heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof has an effect of significantly upregulating the expression activity of bone morphogenetic protein BMP-2, and the anti-osteoporosis effect in vivo
- the results show that the compounds of the present invention have an effect of improving the symptoms of osteoporosis in SAMP6 mice.
- Another object of the present invention is to provide a process for the preparation of a benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
- Step 1) A substituted benzaldehyde having the structure shown in Formula II, a substituted ethyl acetate having the structure shown in Formula VI, is placed in an aprotic solvent, and an inorganic base is added at 0. After stirring at C-60 ° C, the intermediate III is obtained;
- Step 2) When Y in the structure of formula I is O, intermediate III is hydrolyzed in an aqueous alkaline solution, and heated under reflux with a substituted hydroxy compound under the action of a dehydrating agent. After completion of the reaction, separation and purification are carried out to obtain a target.
- Compound IV
- M is OH or N0 2 ;
- X is 0, S or NR 8 ;
- Rj , R 2 , R 3 , , R 5 , R 6 , R 7 , R 8 are as defined in claim 1;
- R 1() is a mercapto group or a halogen; a hydrocarbyloxy group selected from C1 to C18;
- the structural formula VI of the substituted ethyl acetate is:
- Another object of the present invention is to provide a process for the preparation of a benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof, comprising the steps of:
- Step 1) a substituted benzaldehyde having the structure shown in Formula II, a substituted ethyl acetate having the structure shown in Formula VI, is placed in an aprotic solvent, and an inorganic base is added, at 0 ° C to 60 ° C, Stirring reaction Thereafter, intermediate III is obtained;
- Step 2) When Y is 'in the structure of formula I, intermediate III is hydrolyzed in an aqueous alkaline solution, heated under reflux with thionyl chloride to form an acid chloride, and then added at 0 ° C. Obtaining a mixture; at room temperature, the mixture is reacted with a substituted amino compound, after completion of the reaction, separation and purification to obtain the target compound V;
- M is OH or N0 2 ;
- X is 0, S or NR 8 ;
- Ri , R 2 , R 3 , , R 5 , R 6 , R 7 , R 8 are as defined in claim 1;
- R 1Q is fluorenyl or Halogen;
- R n is selected from a C1-C18 alkoxy group; the substituted ethyl acetate has the structural formula VI:
- the aprotic solvent is DMF.
- the inorganic base is anhydrous K 2 C0 3 .
- the alkaline aqueous solution is an aqueous NaOH solution.
- the dehydrating agent is any one of DIC, DMAP or a combination thereof.
- the structure of the substituted hydroxy compound is as shown in Formula VII.
- the acid binding agent is any one of triethylamine and dichloromethane or a combination thereof.
- the structure of the substituted amino compound is as shown in Formula VIII.
- Another object of the present invention is to provide a pharmaceutical composition for anti-osteoporosis, which comprises a therapeutically effective amount of the benzo five-membered unsaturated heterocyclic compound of the present invention or a medicinal use thereof A salt and a pharmaceutically acceptable carrier.
- the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof is contained in the pharmaceutical composition in an amount of 0.1 wt.% to 99.5 wt.%, preferably 0.5 wt.% to 95 wt. .%.
- compositions of the present invention may be in various dosage forms well known in the art, and the dosage form suitable for the present invention is selected from oral preparations, external preparations or injections, preferably oral preparations.
- Oral preparations are selected from the group consisting of tablets, capsules, granules, pills, powders, pills, syrups, lotions, lotions, effervescent, pastes, emulsions, teas, oral solutions, suspensions (dry suspensions or Suspension) or tea, etc.
- external preparations are selected from the group consisting of gels, ointments (sticks, ointments or ointments), tinctures, lotions, spreads, plasters, creams, ointments, suppositories, etc.
- Self-injection (injection) infusion or lyophilized powder needle.
- the compositions of the present invention can be prepared by formulation techniques well known in the art.
- composition of the present invention further comprises a pharmaceutically acceptable carrier, and the amount and type of the pharmaceutically acceptable carrier are determined according to factors such as the physical and chemical properties and content of the active ingredient in the composition, the type of the preparation, the formulation technique, and the like. .
- the pharmaceutically acceptable carriers of the present invention are conventional excipients or adjuvants well known in the art for preparing the above formulations.
- Excipients or excipients commonly used in oral or topical preparations include, but are not limited to, fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, binders, conditioners, solubilizers , antioxidants, bacteriostatic agents, emulsifiers, disintegrators, etc.
- Binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (eg microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose) ), gelatin paste, starch paddle or polyvinylpyrrolidone; fillers such as lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate) , calcium hydrogen phosphate, precipitated calcium carbonate, etc., sorbitol or glycine; lubricants, such as micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrant , for example, starch and its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxyprop
- a buffer composed of (sodium), sodium citrate, sodium phosphate, and disodium hydrogen phosphate; an emulsifier such as polysorbate-80, sorbitan sorbate, pluronic F-68, lecithin , soy lecithin, etc.; solubilizers, such as Tween-80, bile, glycerin, etc.
- the active ingredient may be mixed with a pharmaceutically acceptable controlled release carrier according to the preparation requirements thereof, and then prepared according to a preparation method of a controlled release preparation well known in the art, such as adding a retarder coating or an active agent.
- a preparation method of a controlled release preparation well known in the art, such as adding a retarder coating or an active agent.
- the pellet is prepared into a pellet, such as a sustained-release pellet or a controlled-release pellet;
- the sustained-release carrier includes, but is not limited to, an oil-based admixture, a hydrophilic colloid or a coating retarder.
- the oleaginous incorporation agent is selected from any one or a combination of glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane or dimethyl siloxane; Any one or combination of sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, PVP, gum arabic, scutellaria or carbopol; the coating resistance
- the retardant is selected from the group consisting of ethyl cellulose (EC), hydroxypropylmethyl cellulose (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate phthalate (CAP), acrylic resin, and the like. Or a combination thereof.
- the pharmaceutical composition is prepared in the form of a tablet, a suspension, a capsule, a granule, a pill, a powder, a pill, a syrup, a mixture, a lotion, an effervescent, and a paste.
- Agent emulsion, tea, powder, injection (injection), infusion, gel, plaster, plaster, cream, ointment, tincture, lotion, suppository, smear, ointment, ointment .
- Another object of the present invention is to provide the use of the benzo five-membered unsaturated heterocyclic compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the preparation of a medicament for treating osteoporosis.
- Example 20 6-carboxylic acid methyl ester benzofuran-2 -carboxylic acid (dimethyl 2,-phosphonate) ethyl ester
- 2-hydroxy-4-carboxylic acid methyl ester benzaldehyde (1.80 g, 10 mmol) and anhydrous K 2 C0 under ice bath 3 (1.66 g, 12 mmol) was dissolved in DMF (25 ml). After the dropwise addition was completed, the mixture was stirred at 0 ° C for 30 min, and then reacted in an oil bath at 60 ° C for 12 h.
- N,N-dimethylpropanolamine was used as a raw material and reacted according to the preparation method described in Example 20 to obtain 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid (2'-dimethylamine) propyl ester. (Yield 47%).
- the morpholinoethanol was used as a raw material and reacted according to the preparation method described in Example 20 to give 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid morpholine ethyl ester (yield: 55%).
- Example 26 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid (1,1, -Dimethyl-2-dimethylamine)ethyl ester (Compound 26) was reacted with (1,1 '-dimethyl-2-dimethylamine) ethanol as a starting material according to the preparation method described in Example 20 to obtain Methyl 6-carboxylate benzofuran-2-carboxylic acid (1,1,-dimethyl-2-dimethylamine) ethyl ester (yield 37%).
- Example 27 6-Carboxylic acid methyl ester benzofuran-2-carboxylic acid [4,-(2"-hydroxyethyl) 1 piperazinyl ester (Compound 27) with [4'-(2"-hydroxyl The piperazine ethanol was used as a raw material and reacted according to the preparation method described in Example 20 to obtain 6-carboxylic acid methyl ester benzofuran-2-carboxylic acid [4,-(2"-hydroxyethyl)]piperazine. Ethyl ester (yield 41%).
- Example 29 5,6-Methylenedioxybenzofuran- 2-carboxylic acid (dimethyl 2,-phosphonate) ethyl ester (compound 29) was reacted with dimethyl 2-hydroxyethylphosphonate according to the preparation method described in Example 28 to give 5,6- Methylene dioxybenzofuran-2-carboxylic acid (dimethyl 2,-phosphonate) ethyl ester (yield 45%).
- Example 30 5,6-Methylenedioxybenzofuran-2 -carboxylic acid (2,-dimethylamine) ethyl ester (compound 30) The reaction was carried out according to the preparation method described in Example 28 using N,N-dimethylethanolamine as a starting material to obtain 5,6-methylenedioxybenzofuran-2-carboxylic acid (2,-dimethylamine). Ester (yield 50%).
- the compound 2 was used as a raw material, and then reacted according to the preparation method of Example 42 to give 6-methoxybenzofuran-2-carboxylic acid phosphonic acid ethyl ester (yield: 79%).
- Example 44 6- Methyl carboxylate benzothiophene-2-carboxylic acid (diethyl 2,-phosphonate) methyl ester (compound 44) 2-nitro-4-carboxylic acid methyl ester benzaldehyde (2.00) under ice bath g, 9.56 mmol) and anhydrous K 2 CO 3 (1.50 g, 11.4 mmol) were dissolved in DMF (25 ml), and ethyl acetate (1.15 g, 9.56 mmol) was slowly added dropwise o 0 ° C Stir for 30 min, then react in a 60 ° C oil bath for 10 h.
- Example 53 5,6-Methylenedioxybenzothiophene-2- Carboxylic acid (dimethyl 2,-phosphonate) Ethyl ester (Compound 53) Using dimethyl 2-hydroxyethylphosphonate as a starting material, the reaction was carried out in the same manner as in Example 52 to give 5,6-methylenedioxy Benzothiophene-2-carboxylic acid (dimethyl 2'-phosphonate) ethyl ester (yield 51%).
- Example 56 5,6-methylene Dioxybenzothiophene-2-carboxylic acid [4,-(2"-hydroxyethyl)]piperazine ethyl ester (Compound 56) Using [4,-(2"-hydroxyethyl)]piperazineethanol as a starting material, the reaction of Example 52 gave 5,6-methylenedioxybenzothiophene-2-carboxylic acid [4,- (2"-Hydroxyethyl)]piperazine ethyl ester (yield 39%).
- the morpholine ethyl ester was used as a starting material, and the mixture was subjected to the procedure of Example 52 to give 5,6-methylenedioxybenzothiophene-2-carboxylic acid morpholine ethyl ester (yield: 54%).
- N-methyl-5,6-dimethoxy-indole-2-carboxylic acid and morpholinoethanol were used as raw materials, and reacted according to the method of Example 64 to obtain N-methyl-5,6-dimethoxy.
- the base-B was introduced to the quinone-2-carboxylic acid morpholine ethyl ester (yield: 82%).
- Example 68 N- (2,- Hydroxyethyl)-5-methoxy-indole-2-carboxylic acid (2,-dimethylamine) ethyl ester (compound 68) with N-(2'-hydroxyethyl)-5-methoxy-
- the indole-2-carboxylic acid was used as a starting material, which was reacted according to the procedure of Example 64 to give N-(2,-hydroxyethyl)-5-methoxy-indole-2-carboxylic acid (2,-dimethylamine). Ethyl ester (yield 80%).
- Example 69 N-(2,-methoxy)-6-methoxy-indole-2-carboxylic acid (2,-dimethylamine) ethyl ester (Compound 69) with N-(2'-A The oxy)-6-methoxy-indole-2-carboxylic acid was used as a starting material, which was reacted according to the procedure of Example 64 to give N-(2,-methoxy)-6-methoxy-indole-2. - Carboxylic acid (2,-dimethylamine) ethyl ester (yield 80%).
- N-carboxymethyl-5-methoxy-indole-2-carboxylic acid was used as a starting material, and then reacted according to the method of Example 64 to give N-carboxymethyl-5-methoxy-indole.
- Carboxylic acid (2,-dimethylamine) ethyl ester yield 69%).
- Example 71 5,6-Methylenedioxyphenylpropan-2-carboxylate (2,-dimethylamine) Ethylamine (Compound 71)
- 2-Hydroxy-4,5-methylenedioxybenzaldehyde (3.32 g, 20 mmol) and anhydrous K 2 CO 3 (3.20 g, 24 mmol) were dissolved in DMF (50 ml), and bromoacetic acid B was slowly added dropwise. Ester (3.34 g, 20 mmol). After the dropwise addition was completed, the mixture was stirred at 0 ° C for 30 min, and then reacted in an oil bath at 60 ° C for 14 h.
- reaction mixture was poured into ice water, filtered, and chloroform dissolved solid, dried over anhydrous Na 2 S0 4 , filtered, and evaporated to dryness. After silica gel column chromatography, to obtain a yellow solid 4.00 g (86%).
- the compound 75 was used as a raw material, and reacted according to the method of Example 42 to obtain 5,6-methylenedioxybenzene.
- Example 86 6-Carboxylic acid methyl ester benzofuran-2-carboxylic acid phosphonium ethyl ester (Compound 86) The compound 21 was used as a starting material and reacted according to the method of Example 42 to give methyl 6-carboxylate benzofuran. 2-carboxylic acid phosphonoethyl ester (yield 79%).
- the compound 44 was used as a starting material to give 6-carboxylic acid methyl ester benzothiophene-2-carboxylic acid phosphonomethyl ester (yield: 41%).
- the compound of the present invention can be synthesized stably and reproducibly.
- Experiment 1 In vitro BMP-2 up-regulation activity screening
- a screening model for up-regulating BMP-2 was constructed, and plasmid PYJ was transiently transfected into MC3T3E1 cells.
- the specific process was as follows: 100 ⁇ 7 wells of MC3T3E1 cells were cultured in 96-well sterile plastic culture plates for 8 h. Dilute the appropriate amount of PYJ plasmid DNA in a sterile centrifuge tube with 25 ⁇ 7-well serum-free and anti-anti-DMEM medium. Dilute 0.5 ⁇ ! 7-well LF2000 in 25 ⁇ 7-well serum-free, anti-double-antibody DMEM medium in another sterile centrifuge tube.
- Reagent within 5 mm, combine the above two tubes, incubate for 20 min at room temperature, add the mixed transfection suspension to the above 96-well plate, mix well with each well 50 and then 96-well plate Placed in a 37 ° C carbon dioxide incubator, culture for a certain period of time and then add appropriate concentration of drug-acting cells before fluorescence detection;
- the measurement procedure was as follows: Discard the medium in the 96-well plate, gently rinse the cells with 200 PBS (pH 7.0), completely discard the PBS, add 25 ⁇ 7-well l xPLB, shake at room temperature for 15 min, and allow the cells to Completely lysate, completely aspirate the lysate into the corresponding well of a 96-well white plate for fluorescence analysis, and add 70 ⁇ 7-well analysis reagent LARII to the analysis white plate, immediately (within 5 min), place the analysis whiteboard on the Galaxy spectrophotometer.
- the detection conditions are: no excitation light wavelength, emission light wavelength is empty, Positioning delay is 1.0, Number of intervals 1, Interval time is 1.0s, the shaking mode is set before the instrument reading, and the shaking diameter is 1 mm.
- the up-regulation rate of the sample was calculated using the set positive control, blank control, and associated data and calculation formulas. The results are shown in Table 1.
- Up-regulation rate (sample luminescence - DMSO luminescence) / DMSO luminescence xl00%
- the present invention uses the above BMP-2 screening model to study the up-regulation rate of the compound of formula I of the present invention on BMP-2.
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Abstract
La présente invention concerne un composé benzo-hétérocyclique à 5 chaînons non saturé présentant la structure de formule générale I ou ses sels pharmaceutiquement acceptables, et un procédé de préparation, une composition pharmaceutique et son utilisation. Des expériences ont montré que le composé de la présente invention a pour effet de surréguler l'activité d'expression de la protéine morphogénétique osseuse BMP-2 et l'anti-ostéoporose in vivo, et a également pour effet d'améliorer les symptômes de l'ostéoporose chez les souris SAMP6. Des tests d'activité in vitro ont montré que le composé de la présente invention présente un effet évident de surrégulation sur la protéine morphogénétique osseuse BMP-2.
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WO2008002674A2 (fr) * | 2006-06-29 | 2008-01-03 | Kinex Pharmaceuticals, Llc | Compositions bicycliques et procédés de modulation d'une cascade de kinases |
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